Trial of Rucaparib in Patients With Metastatic Hormone-Sensitive Prostate Cancer Harboring Germline DNA Repair Gene Mutations

With respect to germline mutations, a recent study found that the incidence of inherited
DNA-repair gene alterations in metastatic prostate cancer to be significantly higher (11.8%)
than in both men with localized prostate cancer (4.6%) and in the general population at large
(2.7%). Specifically, mutations in 7 genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, RAD51D, GEN1)
were significantly enriched in patients with metastatic prostate cancer compared to the
general population. These findings suggest that a subset of men are more likely to develop
metastatic prostate cancer (i.e. those with germline mutations in DNA-repair genes) and may
potentially benefit from PARPi therapy.

The clinical activity of PARPi in patients with DNA-repair mutations and metastatic prostate
cancer has now been established. Focusing specifically on patients with a germline mutation
in a pre-specified group of DNA-repair genes, we hypothesize that targeted therapy with PARPi
should be sufficient to induce a clinical response irrespective of hormonal
(castration-sensitive or castration-resistant) status. Our hypothesis is based largely on the
data from Mateo et al showing a clinical response rate of 88% in a heavily pre-treated
population of mCRPC patients with a DNA repair mutation, with the most pronounced responses
being in men with germline inactivation.

For men with mHSPC, this trial would also provide an alternative to ADT. Identification of a
non-hormonal based therapy is warranted as ADT is associated with a shorter time to
castration resistance in men harboring a germline DNA repair mutation versus those with
intact DNA repair. However, given that primary ADT (in mHSPC) is a standard first-line
therapy, all patients on trial must be ineligible for or decline standard-of-care hormonal
treatment. For patients with mHSPC who do not respond to PARPi, we will build safety rules
into the trial design to take patients off study at first signs of progression. Primary ADT
(mHSPC) would still remain a treatment option upon progression.

Inclusion Criteria:

- Willing and able to provide written informed consent and HIPAA authorization for the
release of personal health information.

- Males aged 18 years of age and above

- Histological or cytologic proof of adenocarcinoma of the prostate

- Germline mutation in one or more homologous recombination DNA-repair genes (BRCA1,
BRCA2, ATM, CHEK2, NBN, RAD50, RAD51C, RAD51D, PALB2, MRE11, FANCA, FANCB, FANCC,
FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM) as documented by a clinical
CLIA-grade, genetic test (including but not limited to Invitae, Color Genomics, etc)

- All patients must be ineligible for or have declined androgen deprivation therapy
(ADT)-based systemic treatment

- Absolute PSA ≥2.0 ng/ml at screening.

- Radiographic evidence of metastatic disease by CT scan and bone scan, performed within
the prior 8 weeks.

- Serum testosterone ≥ 100 ng/dl.

- Participants must have normal organ and bone marrow function measured within 28 days
prior to administration of study treatment as defined below:

- Hemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days

- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

- Platelet count ≥ 100 x 109/L

- Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT))
/ Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT))

- Participants must have creatinine clearance estimated using the Cockcroft-Gault
equation of ≥51 mL/min:

- Estimated creatinine clearance = (140-age [years]) x weight (kg) serum creatinine
(mg/dL) x 72

- ECOG Performance Status <2

- Participants must have a life expectancy ≥ 12 months.

- Male participants and their partners, who are sexually active and of childbearing
potential, must agree to the use of two highly effective forms of contraception in
combination [see appendix E for acceptable methods], throughout the period of taking
study treatment and for 6 months after last dose of study drug to prevent pregnancy in
a partner.

Exclusion Criteria:

- Current active second malignancy (history of non-melanoma skin cancers and superficial
bladder cancers are allowed)

- Prior ADT in the past 6 months. Prior ADT in context of neoadjuvant/adjuvant primary
is allowed; prior ADT for biochemical recurrence is also allowed, as long as no ADT
has been administered in past 6 months and testosterone has recovered (>100 ng/dl).
The total duration of prior ADT should not exceed 24 months.

- Prior oral anti-androgen (e.g. bicalutamide, nilutamide, enzalutamide, apalutamide),
or androgen synthesis inhibitor (e.g. abiraterone, orteronel) in the past 6 months is
not permitted. 5-alpha reductase inhibitor therapy (e.g. finasteride, dutasteride) is
allowed, as long as subject has been stable on medication for past 6 months.

- Presence of visceral (i.e. lung or liver) metastases >3cm in long-axis dimension.

- Pain due to bone metastases requiring narcotic analgesics.

- Prior treatment with intravenous chemotherapy.

- Use of any prohibited concomitant medications (Appendix B: Medications With the
Potential for Drug-Drug Interactions) within the prior 2 weeks.

- Involvement in the planning and/or conduct of the study (applies to both Clovis
Oncology staff and/or staff at the study site)

- Previous enrollment in the present study

- Participation in another clinical study with an investigational product during the
last 1 month.

- Any previous treatment with a PARP inhibitor, including rucaparib.

- Resting ECG with QTc > 480 msec on 2 or more time points within a 24 hour period or
family history of long QT syndrome

- Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 2)
caused by previous cancer therapy, excluding alopecia.

- Patients with myelodysplastic syndrome/acute myeloid leukemia or with features
suggestive of MDS/AML.

- Major surgery within 2 weeks of starting study treatment, and patients must have
recovered from any effects of any major surgery.

- Poor medical risk due to a serious, uncontrolled medical disorder, non-malignant
systemic disease or active, uncontrolled infection. Examples include, but are not
limited to, uncontrolled ventricular arrhythmia, recent (within 6 months) myocardial
infarction, uncontrolled major seizure disorder, extensive interstitial bilateral lung
disease, or any psychiatric disorder that prohibits obtaining informed consent.

- Unable to swallow orally administered medication or gastrointestinal disorders likely
to interfere with absorption of the study medication.

- Immunocompromised patients, e.g., patients who are known to be serologically positive
for HIV. Known active hepatitis (i.e. Hepatitis B or C) due to risk of transmitting
the infection through blood or other body fluids

- Known hypersensitivity to rucaparib or any of the excipients of the product.

- Whole blood transfusions in the last 30 days prior to entry to the study.